This project involves the role of bradykinin in the pulmonary vasculature during hypoxia, normoxia and hyperoxia. In addition, the pathophysologic effects of bradykinin in endotoxemia are being examined. The angiotensin converting enzyme inhibitor, SQ 20881, which also inhibits bradykininase, has been shown to reduce the pulmonary pressor response to hypoxia in the anesthetized dog. However, another agent (SQQ 14225), which is thought to have the same actions, did not reduce the pressor response to hypoxia in other dogs. The reason for this discrepancy is now being investigated. The administration of SQ 14225 (5mg/kg/day) in the feed of maternal rabbits, maintained at a simulated altitude of 3,500 m, resulted in 100% fetal mortality. This preliminary experiment is being repeated with larger numbers of rabbits and appropriate controls. The adminstration of meclofenamate has been found to protect the pulmonary vascular endothelium of the intact anesthetized dog against infused endotoxin (either 1mg/kg or 15 micrograms/kg), as shown by a reduction in platelet and leucocyte aggregation on electron microscopy. The possible therapeutic implications of this finding are being studied.